Targeting the GPC2 oncoprotein with immune-based therapies in neuroblastoma

项目摘要/摘要 我的职业目标是成为一名内科科学家，专注于将新的实验室发现转化为 儿童高危实体瘤的安全有效治疗。这份提案描述了一个5- 年计划，旨在通过以下途径促进我发展成为一名独立的翻译医生-科学家 获得关键技术技能，与教学培训和全面指导相结合 宾夕法尼亚大学(宾夕法尼亚大学)和儿童医院的不同终身教职员工团队 费城(印章)。我将在以下杰出和成熟的指导下进行拟议的研究 约翰·马里斯博士，翻译神经母细胞瘤研究的国际领先者。另外，我敬爱的 咨询委员会由在癌症方面拥有不同专业知识的备受尊敬的内科科学家组成 生物学和免疫疗法。最后，科学协作、资源丰富的研究环境 佩恩和乔普为进行这些翻译研究提供了一个理想的环境。 建议的研究重点是信号共受体Glypcan-2(GPC2)。我们的实验室有 发现GPC2是连接到神经母细胞瘤细胞外表面的糖磷脂酰肌醇(GPI)， 但在大多数正常的儿科组织中没有发现。我还发现神经母细胞瘤依赖于 关于GPC2对肿瘤生长的影响。为了利用GPC2的S差异表达，我进行了概念验证 神经母细胞瘤患者来源的异种移植(PDX)小鼠模型的体内疗效研究表明 GPC2靶向抗体药物结合物(ADC；D3-GPC2-PBD)可导致肿瘤持续消退。这个 恶性机制和选择性靶向其他Glypicans的能力，如GPC3，基于免疫 治疗方法已经得到了充分的研究。但GPC2的S促肿瘤作用，与GPC2的适合性有关 作为免疫治疗的安全和有效的靶点，以及基于免疫的最佳治疗方法 目标GPC2，目前全部仍未确定。我推测GPC2是致癌的关键调节因子 神经母细胞瘤中的信号通路，鉴于其强大的差异表达，是理想的细胞表面 基于免疫的治疗方法的分子。因此，我建议(1)定义潜在的机制 神经母细胞瘤中GPC2细胞表面异常表达和致瘤性，(2)决定疗效和 D3-GPC2-PBD ADC在神经母细胞瘤中的安全性概况，以及(3)工程师GPC2重定向嵌合体 抗原受体(CAR)T细胞，并确定其在神经母细胞瘤中的疗效。总而言之，我将利用 我的导师和咨询委员会的智力力量和过往记录，以及专业知识， 实验室设施，以及CHOP和宾夕法尼亚大学可用的科学资源，以成功实现这一目标 提出研究和职业发展计划。这些努力将为我的 作为一名内科科学家的职业生涯和开发一个独立的翻译研究项目。

PROJECT SUMMARY/ABSTRACT My career goals are to become a physician-scientist focused on translating novel laboratory discoveries into safe and efficacious therapies for children with high-risk pediatric solid tumors. This proposal describes a 5- year plan designed to facilitate my development into an independent translational physician-scientist through the acquisition of critical technical skills, integrated with didactic training and comprehensive mentoring from a diverse team of tenured faculty members at the University of Pennsylvania (Penn) and the Children’s Hospital of Philadelphia (CHOP). I will conduct the proposed studies under the outstanding and proven mentorship of Dr. John Maris, an international leader in translational neuroblastoma research. Additionally, my dedicated Advisory Committee is comprised of highly regarded physician-scientists with diverse expertise in cancer biology and immunotherapy. Finally, the scientifically collaborative, resource-rich research environment at Penn and CHOP provides an ideal setting to conduct these translational studies. The proposed research focuses on the signaling co-receptor glypican-2 (GPC2). Our laboratory has discovered that GPC2 is glycophosphatidylinositol (GPI)-linked to the extracellular surface of neuroblastomas, but is not found on a majority of normal pediatric tissues. I have also found that neuroblastomas are dependent on GPC2 for tumor growth. To capitalize on GPC2’s differential expression, I have performed proof-of-concept in vivo efficacy studies in neuroblastoma patient-derived xenograft (PDX) murine models showing that a GPC2-targeted antibody drug conjugate (ADC; D3-GPC2-PBD) results in sustained tumor regression. The malignant mechanisms and the ability to selectively target other glypicans, such as GPC3, with immune-based therapies have been well-studied. However, GPC2’s role in promoting tumorigenesis, the suitability of GPC2 as a safe and effective target for immunotherapeutics, and the optimal immune-based therapy approach to target GPC2, all currently remain undefined. I hypothesize that GPC2 is a critical regulator of oncogenic signaling pathways in neuroblastoma and, given its robust differential expression, is an ideal cell surface molecule for immune-based therapeutic approaches. Thus, I propose to (1) Define the mechanisms underlying aberrant GPC2 cell surface expression and oncogenicity in neuroblastoma, (2) Determine the efficacy and safety profile of the D3-GPC2-PBD ADC in neuroblastoma, and (3) Engineer GPC2-redirected chimeric antigen receptor (CAR) T cells and establish their efficacy in neuroblastoma. In summary, I will take advantage of the intellectual strength and track-record of my mentor and Advisory Committee, as well as the expertise, laboratory facilities, and scientific resources available at CHOP and Penn to successfully accomplish this proposed research and career development plan. These efforts will provide an outstanding foundation for my career as a physician-scientist and the development of an independent translational research program.